Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that regulates T-cell and natural killer-cell responses, induces the production of interferon-γ (IFN-γ), favours the differentiation of T helper 1 (TH1) cells and is an important link between innate resistance and adaptive immunity.
Although phagocytes were reported originally to be the main cell types that produce IL-12, subsets of dendritic cells (DCs) are the first producers of IL-12 in response to pathogens during infections.
The differential production of IL-12 by DC subsets in response to various pathogens is dependent on differences in the regulation of expression of the gene encoding IL-12, patterns of Toll-like receptor (TLR) expression, and cross-regulation between the different subsets, involving cytokines such as IL-10 and type I IFN.
Maturation of CD4+ and CD8+ T cells into type-1 cytokine-producing cells is differentially regulated, indicating the different relative roles of IL-12 and other factors in favouring maturation of the two cell types.
Recently, it has become evident, however, that TH1 responses might take place in the absence of IL-12 and that IL-12 might be only one of the members of a family of heterodimeric cytokines, also including IL-23 and IL-27, that are involved in the regulation of TH1 responses.
Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-γ (IFN-γ), favours the differentiation of T helper 1 (TH1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for TH1 responses. Our understanding of the relative roles of IL-12 and other factors in TH1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.
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Janeway, C. A. Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16 (1992).
Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588–593 (1998).
Lertmemongkolchai, G., Cai, G., Hunter, C. A. & Bancroft, G. J. Bystander activation of CD8+ T cells contributes to the rapid production of IFN-γ in response to bacterial pathogens. J. Immunol. 166, 1097–1105 (2001). This paper reports important experimental evidence in vivo in support of the concept that antigen-non-specific bystander T cells have an important role in the early production of pro-inflammatory cytokines in innate resistance.
Cui, J. et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).
Ohteki, T. et al. Interleukin-12-dependent interferon-γ production by CD8α+ lymphoid dendritic cells. J. Exp. Med. 189, 1981–1986 (1999).
Airoldi, I. et al. Expression and function of IL-12 and IL-18 receptors on human tonsillar B cells. J. Immunol. 165, 6880–6888 (2000).
Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
Le Gros, G., Ben-Sasson, S. Z., Seder, R., Finkelman, F. D. & Paul, W. E. Generation of interleukin-4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172, 921–929 (1990).
Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–846 (1989). This paper reports the first identification of IL-12, its functions and its heterodimeric structure.
Hsieh, C. S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993). This study was the first to show the pivotal role of IL-12 in T H 1-cell differentiation in the mouse.
Manetti, R. et al. Natural killer cell stimulatory factor (interleukin-12 [IL-12]) induces T helper type 1 (TH1)-specific immune responses and inhibits the development of IL-4-producing TH cells. J. Exp. Med. 177, 1199–1204 (1993). This study was the first demonstration of the ability of IL-12 to induce the differentiation of T H 1-cell clones.
Stern, A. S. et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc. Natl Acad. Sci. USA 87, 6808–6812 (1990).
D'Andrea, A. et al. Production of natural killer cell stimulatory factor (interleukin-12) by peripheral-blood mononuclear cells. J. Exp. Med. 176, 1387–1398 (1992).
Macatonia, S. E. et al. Dendritic cells produce IL-12 and direct the development of TH1 cells from naive CD4+ T cells. J. Immunol. 154, 5071–5079 (1995). This paper describes how dendritic cells (DCs) induce T H 1-cell differentiation by producing IL-12 in response to antigen-activated T cells.
Merberg, D. M., Wolf, S. F. & Clark, S. C. Sequence similarity between NKSF and the IL-6/G-CSF family. Immunol. Today 13, 77–78 (1992).
Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000). This study reports the identification of IL-23.
Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and novel p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002). This study reports the identification of IL-27.
Presky, D. H. et al. A functional interleukin-12 receptor complex is composed of two β-type cytokine receptor subunits. Proc. Natl Acad. Sci. USA 93, 14002–14007 (1996).
Thierfelder, W. E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).
Kaplan, M. H., Sun, Y. L., Hoey, T. & Grusby, M. J. Impaired IL-12 responses and enhanced development of TH2 cells in Stat4-deficient mice. Nature 382, 174–177 (1996).
Grohmann, U. et al. IL-12 acts directly on DC to promote nuclear localization of NF-κB and primes DC for IL-12 production. Immunity 9, 315–323 (1998).
Rogge, L. et al. Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J. Exp. Med. 185, 825–831 (1997).
Szabo, S. J., Dighe, A. S., Gubler, U. & Murphy, K. M. Regulation of the interleukin (IL)-12R β2-subunit expression in developing T helper 1 (TH1) and TH2 cells. J. Exp. Med. 185, 817–824 (1997). References 22 and 23 show, in humans and in mice, that unresponsiveness of T H 2 cells to IL-12 is owing to down-regulation of expression of IL-12Rβ2.
Wysocka, M. et al. Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25, 672–676 (1995).
Carra, G., Gerosa, F. & Trinchieri, G. Biosynthesis and posttranslational regulation of human IL-12. J. Immunol. 164, 4752–4761 (2000).
Gillessen, S. et al. Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. Eur. J. Immunol. 25, 200–206 (1995).
Heinzel, F. P., Hujer, A. M., Ahmed, F. N. & Rerko, R. M. In vivo production and function of IL-12 p40 homodimers. J. Immunol. 158, 4381–4388 (1997).
Sousa, C. R. et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin-12 by dendritic cells and their redistribution to T-cell areas. J. Exp. Med. 186, 1819–1829 (1997).
Gazzinelli, R. T. et al. Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J. Immunol. 153, 2533–2543 (1994). This study describes the central role of IL-12 in resistance to intracellular parasites, both in wild-type and SCID mice, and shows the participation of this cytokine in the mechanism of T-cell-independent macrophage activation.
Scharton-Kersten, T. M. et al. In the absence of endogenous IFN-γ, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157, 4045–4054 (1996).
Schulz, O. et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000).
Dalod, M. et al. Interferon-α/β and interleukin-12 responses to viral infections: pathways regulating dendritic-cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002). This study reports that in response to virus infection in vivo, mouse type-I IFN-producing cells synthesize both IFN-α and IL-12, and that different subsets of DC produce IL-12 in response to bacterial and viral infections.
Ma, X., Neurath, M., Gri, G. & Trinchieri, G. Identification and characterization of a novel Ets-2-related nuclear complex implicated in the activation of the human interleukin-12 p40 gene promoter. J. Biol. Chem. 272, 10389–10395 (1997).
Aliberti, J. et al. CCR5 provides a signal for microbial-induced production of IL-12 by CD8α+ dendritic cells. Nature Immunol. 1, 83–87 (2000).
Grumont, R. et al. c-Rel regulates interleukin-12 p70 expression in CD8+ dendritic cells by specifically inducing p35 gene transcription. J. Exp. Med. 194, 1021–1032 (2001). This paper identifies a differential requirement for c-REL for transcription of the genes encoding IL-12 p35 and p40 in DCs and macrophages, respectively.
Wolf, S. F. et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J. Immunol. 146, 3074–3081 (1991). This study reports the cloning of the genes encoding the two chains of IL-12.
Ma, X. & Trinchieri, G. Regulation of interleukin-12 production in antigen-presenting cells. Adv. Immunol. 79, 55–92 (2001).
Snijders, A. et al. Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit. J. Immunol. 156, 1207–1212 (1996).
Jarrossay, D., Napolitani, G., Colonna, M., Sallusto, F. & Lanzavecchia, A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur. J. Immunol. 31, 3388–3393 (2001).
Kadowaki, N. et al. Subsets of human dendritic-cell precursors express different Toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).
Hayes, M. P., Murphy, F. J. & Burd, P. R. Interferon-γ-dependent inducible expression of the human interleukin-12 p35 gene in monocytes initiates from a TATA-containing promoter distinct from the CpG-rich promoter active in Epstein–Barr virus-transformed lymphoblastoid cells. Blood 91, 4645–4651 (1998).
Ma, X. et al. The interleukin-12 p40 gene promoter is primed by interferon-γ in monocytic cells. J. Exp. Med. 183, 147–157 (1996).
D'Andrea, A., Ma, X., Aste-Amezaga, M., Paganin, C. & Trinchieri, G. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral-blood mononuclear cells: priming for IL-12 and tumor-necrosis factor-α production. J. Exp. Med. 181, 537–546 (1995).
Marshall, J. D., Robertson, S. E., Trinchieri, G. & Chehimi, J. Priming with IL-4 and IL-13 during HIV-1 infection restores in vitro IL-12 production by mononuclear cells of HIV-infected patients. J. Immunol. 159, 5705–5714 (1997).
Cella, M. et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T-cell stimulatory capacity: T–T help via APC activation. J. Exp. Med. 184, 747–752 (1996).
Kalinski, P. et al. IL-4 is a mediator of IL-12p70 induction by human TH2 cells: reversal of polarized TH2 phenotype by dendritic cells. J. Immunol. 165, 1877–1881 (2000).
Kato, T., Hakamada, R., Yamane, H. & Nariuchi, H. Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40–CD40 ligand interaction. J. Immunol. 156, 3932–3938 (1996).
Vaidyanathan, H., Gentry, J. D., Weatherman, A., Schwartzbach, S. D. & Petro, T. M. Differential response of the murine IL-12 p35 gene to lipopolysaccharide compared with interferon-γ and CD40 ligation. Cytokine 16, 1–9 (2001).
Gerosa, F. et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327–333 (2002).
Aste-Amezaga, M., Ma, X., Sartori, A. & Trinchieri, G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J. Immunol. 160, 5936–5944 (1998).
D'Andrea, A. et al. Interleukin-10 inhibits human lymphocyte IFN-γ production by suppressing natural killer cell stimulatory factor/interleukin-12 synthesis in accessory cells. J. Exp. Med. 178, 1041–1048 (1993).
Jankovic, D. et al. In the absence of IL-12, CD4+ T-cell responses to intracellular pathogens fail to default to a TH2 pattern and are host protective in an IL-10(−/−) setting. Immunity 16, 429–439 (2002). This study shows that during an infection, T H 1 cells that produce low levels of IFN-γ can be generated in the absence of IL-12, but not in the absence of signalling through Toll-like receptors. The T H 1 cells that are generated in the absence of IL-12 cannot protect the animals unless the animals are also deficient for IL-10.
Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).
Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194, 1497–1506 (2001).
Du, C. & Sriram, S. Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-β in ANA-1 cells. J. Leukocyte Biol. 64, 92–97 (1998).
Cousens, L. P. et al. Two roads diverged: interferon α/β- and interleukin-12-mediated pathways in promoting T-cell interferon-γ responses during viral infection. J. Exp. Med. 189, 1315–1328 (1999). This study indicates the roles of both IL-12 and IFN-α in IFN-γ production in the mouse, and the cross-regulation of these two cytokines.
Braun, M. C. & Kelsall, B. L. Regulation of interleukin-12 production by G-protein-coupled receptors. Microbes Infect. 3, 99–107 (2001).
van der Pouw Kraan, T. C., Boeije, L. C., Smeenk, R. J., Wijdenes, J. & Aarden, L. A. Prostaglandin-E2 is a potent inhibitor of human interleukin-12 production. J. Exp. Med. 181, 775–779 (1995).
Weinmann, A. S. et al. Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event. Nature Immunol. 2, 51–57 (2001).
Hayes, M. P., Wang, J. & Norcross, M. A. Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-γ of lipopolysaccharide-inducible p35 and p40 genes. Blood 86, 646–650 (1995).
Tone, Y. et al. Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes. Eur. J. Immunol. 26, 1222–1227 (1996).
Yoshimoto, T. et al. Molecular cloning and characterization of murine IL-12 genes. J. Immunol. 156, 1082–1088 (1996).
Babik, J. M. et al. Expression of murine IL-12 is regulated by translational control of the p35 subunit. J. Immunol. 162, 4069–4078 (1999).
Murphy, F. J., Hayes, M. P. & Burd, P. R. Disparate intracellular processing of human IL-12 preprotein subunits: atypical processing of the P35 signal peptide. J. Immunol. 164, 839–847 (2000).
Trinchieri, G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv. Immunol. 70, 83–243 (1998).
Piccotti, J. R. et al. Alloantigen-reactive TH1 development in IL-12-deficient mice. J. Immunol. 160, 1132–1138 (1998).
Cooper, A. M. et al. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168, 1322–1327 (2002).
Becher, B., Durell, B. G. & Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).
Perussia, B. et al. Natural killer (NK)-cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-αβ+, TCR-γδ+ T lymphocytes, and NK cells. J. Immunol. 149, 3495–3502 (1992).
Kubin, M., Kamoun, M. & Trinchieri, G. Interleukin-12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J. Exp. Med. 180, 211–222 (1994).
Murphy, E. E. et al. B7 and interleukin-12 cooperate for proliferation and interferon-γ production by mouse T helper clones that are unresponsive to B7 costimulation. J. Exp. Med. 180, 223–231 (1994). References 70 and 71 show that in both humans and mice, IL-12 is strongly synergistic with co-stimulatory signals (such as B7–CD28 interactions) for inducing IFN-γ production by and proliferation of both resting and activated T cells, even in the absence of antigen.
Chan, S. H. et al. Induction of IFN-γ production by NK-cell stimulatory factor (NKSF): characterization of the responder cells and synergy with other inducers. J. Exp. Med. 173, 869–879 (1991).
Hunter, C. A., Chizzonite, R. & Remington, J. S. IL-1β is required for IL-12 to induce production of IFN-γ by NK cells. A role for IL-1β in the T-cell-independent mechanism of resistance against intracellular pathogens. J. Immunol. 155, 4347–4354 (1995).
Chan, S. H., Kobayashi, M., Santoli, D., Perussia, B. & Trinchieri, G. Mechanisms of IFN-γ induction by natural killer cell stimulatory factor (NKSF/IL-12): role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J. Immunol. 148, 92–98 (1992).
Walker, W., Aste-Amezaga, M., Kastelein, R. A., Trinchieri, G. & Hunter, C. A. IL-18 and CD28 use distinct molecular mechanisms to enhance NK-cell production of IL-12-induced IFN-γ. J. Immunol. 162, 5894–5901 (1999).
Hodge, D. L., Martinez, A., Julias, J. G., Taylor, L. S. & Young, H. A. Regulation of nuclear γ-interferon gene expression by interleukin-12 (IL-12) and IL-2 represents a novel form of posttranscriptional control. Mol. Cell. Biol. 22, 1742–1753 (2002).
Okamura, H., Tsutsui, H., Kashiwamura, S., Yoshimoto, T. & Nakanishi, K. Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Adv. Immunol. 70, 281–312 (1998).
Bazan, J. F., Timans, J. C. & Kastelein, R. A. A newly defined interleukin-1? Nature 379, 591 (1996).
Barbulescu, K. et al. IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-γ promoter in primary CD4+ T lymphocytes. J. Immunol. 160, 3642–3647 (1998).
Nakahira, M. et al. Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J. Immunol. 168, 1146–1153 (2002).
Chang, J. T., Segal, B. M., Nakanishi, K., Okamura, H. & Shevach, E. M. The costimulatory effect of IL-18 on the induction of antigen-specific IFN-γ production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor β2-subunit. Eur. J. Immunol. 30, 1113–1119 (2000).
Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both TH1 and TH2 responses. Annu. Rev. Immunol. 19, 423–474 (2001).
Yang, J., Murphy, T. L., Ouyang, W. & Murphy, K. M. Induction of interferon-γ production in TH1 CD4+ T cells: evidence for two distinct pathways for promoter activation. Eur. J. Immunol. 29, 548–555 (1999).
Wu, C. Y., Gadina, M., Wang, K., O'Shea, J. & Seder, R. A. Cytokine regulation of IL-12 receptor-β2 expression: differential effects on human T and NK cells. Eur. J. Immunol. 30, 1364–1374 (2000).
Sareneva, T., Julkunen, I. & Matikainen, S. IFN-α and IL-12 induce IL-18 receptor gene expression in human NK and T cells. J. Immunol. 165, 1933–1938 (2000).
Park, W. R. et al. CD28 costimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells. Eur. J. Immunol. 31, 1456–1464 (2001).
Elloso, M. M. & Scott, P. Differential requirement of CD28 for IL-12 receptor expression and function in CD4+ and CD8+ T cells. Eur. J. Immunol. 31, 384–395 (2001).
Carter, L. L. & Murphy, K. M. Lineage-specific requirement for signal transducer and activator of transcription (Stat)4 in interferon-γ production from CD4+ versus CD8+ T cells. J. Exp. Med. 189, 1355–1360 (1999).
Afonso, L. C. et al. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263, 235–237 (1994).
Seder, R. A., Gazzinelli, R., Sher, A. & Paul, W. E. Interleukin-12 acts directly on CD4+ T cells to enhance priming for interferon-γ production and diminishes interleukin-4 inhibition of such priming. Proc. Natl Acad. Sci. USA 90, 10188–10192 (1993).
Manetti, R. et al. Interleukin-12 induces stable priming for interferon-γ (IFN-γ) production during differentiation of human T helper (TH) cells and transient IFN-γ production in established TH2-cell clones. J. Exp. Med. 179, 1273–1283 (1994).
Gerosa, F. et al. Interleukin-12 primes human CD4 and CD8 T-cell clones for high production of both interferon-γ and interleukin-10. J. Exp. Med. 183, 2559–2569 (1996).
Macatonia, S. E., Hsieh, C. S., Murphy, K. M. & O'Garra, A. Dendritic cells and macrophages are required for TH1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-γ production is IFN-γ-dependent. Int. Immunol. 5, 1119–1128 (1993).
Noble, A., Thomas, M. J. & Kemeny, D. M. Early TH1/TH2 cell polarization in the absence of IL-4 and IL-12: T-cell receptor signaling regulates the response to cytokines in CD4 and CD8 T cells. Eur. J. Immunol. 31, 2227–2235 (2001).
Chen, Q. et al. Development of TH1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).
Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000). This study identifies the transcription factor T-bet as an important element in T H 1-cell commitment.
Mullen, A. C. et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907–1910 (2001). This paper shows that the appearance of T-bet in committed T H 1 cells precedes exposure to IL-12, indicating that IL-12 might have a role more in the fixation and amplification of T H 1 cells than in their commitment.
Heath, V. L. et al. Cutting edge: ectopic expression of the IL-12 receptor-β2 in developing and committed TH2 cells does not affect the production of IL-4 or induce the production of IFN-γ. J. Immunol. 164, 2861–2865 (2000).
Lighvani, A. A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl Acad. Sci. USA 98, 15137–15142 (2001).
Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol. 3, 549–557 (2002).
Szabo, S. J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002). This study characterizes the role of T-bet in T H 1-cell differentiation in vivo in mice that are genetically deficient for T-bet, identifying a requirement for T-bet for the differentiation of type-1 CD4+, but not CD8+, cells.
Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).
Wiekowski, M. T. et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J. Immunol. 166, 7563–7570 (2001).
Devergne, O. et al. A novel interleukin-12 p40-related protein induced by latent Epstein–Barr virus infection in B lymphocytes. J. Virol. 70, 1143–1153 (1996).
Devergne, O., Coulomb-L'Hermine, A., Capel, F., Moussa, M. & Capron, F. Expression of Epstein–Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. Am. J. Pathol. 159, 1763–1776 (2001).
Christ, A. D. et al. An interleukin-12-related cytokine is up-regulated in ulcerative colitis but not in Crohn's disease. Gastroenterology 115, 307–313 (1998).
Huang, Q. et al. The plasticity of dendritic-cell responses to pathogens and their components. Science 294, 870–875 (2001).
Murphy, T. L., Cleveland, M. G., Kulesza, P., Magram, J. & Murphy, K. M. Regulation of interleukin-12 p40 expression through an NF-κB half-site. Mol. Cell. Biol. 15, 5258–5267 (1995).
Plevy, S. E., Gemberling, J. H. M., Hsu, S., Dorner, A. J. & Smale, S. T. Multiple control elements mediate activation of the murine and human interleukin-12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Mol. Cell. Biol. 17, 4572–4588 (1997).
Becker, C. et al. Regulation of IL-12 p40 promoter activity in primary human monocytes: roles of NF-κB, CCAAT/enhancer-binding protein-β, and PU. 1 and identification of a novel repressor element (GA-12) that responds to IL-4 and prostaglandin E(2). J. Immunol. 167, 2608–2618 (2001).
Gorgoni, B., Maritano, D., Marthyn, P., Righi, M. & Poli, V. C/EBPβ gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages. J. Immunol. 168, 4055–4062 (2002).
Gri, G., Savio, D., Trinchieri, G. & Ma, X. Synergistic regulation of the human interleukin-12 p40 promoter by NF-κB and Ets transcription factors in Epstein–Barr virus-transformed B cells and macrophages. J. Biol. Chem. 273, 6431–6438 (1998).
Salkowski, C. A. et al. IL-12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice. J. Immunol. 163, 1529–1536 (1999).
Cappiello, M. G., Sutterwala, F. S., Trinchieri, G., Mosser, D. M. & Ma, X. Suppression of IL-12 transcription in macrophages following Fcγ receptor ligation. J. Immunol. 166, 4498–4506 (2001).
Wang, I. M. et al. An IFN-γ-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J. Immunol. 165, 271–279 (2000).
D'Ambrosio, D. et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252–262 (1998).
Delgado, M. & Ganea, D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor-κB and Ets activation. J. Biol. Chem. 274, 31930–31940 (1999).
Maruo, S. et al. IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T-helper cell clones. J. Immunol. 156, 1748–1755 (1996).
Seder, R. A., Kelsall, B. L. & Jankovic, D. Differential roles for IL-12 in the maintenance of immune responses in infectious versus autoimmune disease. J. Immunol. 157, 2745–2748 (1996).
Yap, G., Pesin, M. & Sher, A. Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen Toxoplasma gondii. J. Immunol. 165, 628–631 (2000).
Park, A. Y., Hondowicz, B. D. & Scott, P. IL-12 is required to maintain a TH1 response during Leishmania major infection. J. Immunol. 165, 896–902 (2000).
Orange, J. S., Wang, B., Terhorst, C. & Biron, C. A. Requirement for natural killer cell-produced interferon-γ in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin-12 administration. J. Exp. Med. 182, 1045–1056 (1995).
Monteiro, J. M., Harvey, C. & Trinchieri, G. Role of interleukin-12 in primary influenza virus infection. J. Virol. 72, 4825–4831 (1998).
Geng, Y., Berencsi, K., Gyulai, Z., Valgi-Nagy, T., Gonczol, E. & Trinchieri, G. Roles of interleukin-12 and interferon-γ in murine Chlamydia pneumoniae infection. Infect. Immun. 68, 2245–2253 (2000).
Penttila, J. M. et al. Local immune responses to Chlamydia pneumoniae in the lungs of BALB/c mice during primary infection and reinfection. Infect. Immun. 66, 5113–5118 (1998).
Rogge, L. et al. The role of Stat4 in species-specific regulation of TH-cell development by type I IFNs. J. Immunol. 161, 6567–6574 (1998).
Farrar, J. D. et al. Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nature Immunol. 1, 65–69 (2000).
Matikainen, S. et al. IFN-α and IL-18 synergistically enhance IFN-γ production in human NK cells: differential regulation of Stat4 activation and IFN-γ gene expression by IFN-α and IL-12. Eur. J. Immunol. 31, 2236–2245 (2001).
Fallarino, F., Uyttenhove, C., Boon, T. & Gajewski, T. F. Endogenous IL-12 is necessary for rejection of P815 tumor variants in vivo. J. Immunol. 156, 1095–1100 (1996).
Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).
Brunda, M. J. et al. Antitumor and antimetastatic activity of interleukin-12 against murine tumors. J. Exp. Med. 178, 1223–1230 (1993).
Noguchi, Y., Jungbluth, A., Richards, E. C. & Old, L. J. Effect of interleukin-12 on tumor induction by 3-methylcholanthrene. Proc. Natl Acad. Sci. USA 93, 11798–11801 (1996).
Nanni, P. et al. Combined allogeneic tumor-cell vaccination and systemic interleukin-12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J. Exp. Med. 194, 1195–1205 (2001).
Colombo, M. P. & Trinchieri, G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13, 155–168 (2002).
Voest, E. E. et al. Inhibition of angiogenesis in vivo by interleukin-12. J. Natl Cancer Inst. 87, 581–586 (1995).
Yao, L. et al. Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood 96, 1900–1905 (2000).
Gee, M. S. et al. Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. Cancer Res. 61, 2974–2982 (2001).
Quaglino, E. et al. Immunological prevention of spontaneous tumors: a new prospect? Immunol. Lett. 80, 75–79 (2002).
Taga, T. & Kishimoto, T. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819 (1997).
Kawashima, T., Kawasaki, H., Kitamura, T., Nojima, Y. & Morimoto, C. Interleukin-12 induces tyrosine phosphorylation of an 85-kDa protein associated with the interleukin-12 receptor-β1 subunit. Cell. Immunol. 186, 39–44 (1998).
I thank R. Kastelein, X.-J. Ma and K. Murphy for discussions and for sharing of unpublished data.
(IFNs). Proteins with potent antiviral activity that are of particular importance during the early response to pathogens. Type I or viral IFNs comprise families (α, β and ω) of homologous proteins that interact with a common two-chain receptor (composed of IFNAR1 and IFNAR2), and type II or immune IFN is represented by a single protein (IFN-γ) that interacts with a different two-chain receptor (composed of IFN-γR1 and IFN-γR2).
- TOLL-LIKE RECEPTORS
(TLRs). Receptors present on mammalian cells, mostly on cells that are involved in innate or adaptive resistance to pathogens, that are homologous to the Toll-receptor gene family in Drosophila, members of which have important roles in both embryogenesis and defence against infection. TLRs have evolved to recognize pathogen-associated molecular patterns (PAMPs) that are conserved between and shared by many microbial pathogens.
- T HELPER 1/2
(TH1/TH2). Functional subsets of CD4+ T cells expressing T-cell receptor-αβ that produce either type-1 cytokines (IL-2, IFN-γ and other cytokines that support macrophage activation, the generation of cytotoxic T cells and the production of opsonizing antibodies) or type-2 cytokines (IL-4, IL-5, IL-13 and other cytokines that support B-cell activation, the production of non-opsonizing antibodies, allergic reactions and the expulsion of extracellular parasites).
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Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3, 133–146 (2003). https://doi.org/10.1038/nri1001
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